Thebaine is an opiate alkaloid. While thebaine is not used therapeutically itself, it can be converted industrially into a variety of therapeutically important opiate alkaloids including oxycodone, oxymorphone, nalbuphine, naloxone, naltrexone, diprenorphine, buprenorphine and etorphine. Buprenorphine, for example, is a thebaine derivative with powerful analgesia approximately twenty-five to forty times as potent as morphine, and is indicated for the treatment of moderate to severe chronic pain or for pre-operative analgesia.
Buprenorphine is made via a synthetic route that starts with the conversion of thebaine to 6,14-endo-etheno-7-α-acetyltetrahydro-thebaine. In particular, thebaine has been reacted with a dienophile (e.g., methyl vinyl ketone) in the presence of an alcohol to produce the Diels Alder product 6,14-endo-etheno-7α-acetyltetrahydro-thebaine. The Diels Alder product is then hydrogenated to produce 7-acetyl-6,14-endoethano-6,7,8,14-tetrahydrothebaine.
Several of the synthetic routes used to produce 7-acetyl-6,14-endoethano-6,7,8,14-tetrahydrothebaine present serious disadvantages. For example, U.S. Pat. No. 5,849,915 ('915 patent) describes a process for forming buprenorphine that includes reacting thebaine with an excess of methyl vinyl ketone in a Diels-Alder step. The excess unsaturated ketone is removed after the reaction by distillation under reduced pressure. The residue produced in this step is dissolved in boiling methanol, which was then cooled to produce a crystalline solid, which is filtered and washed with cool methanol, and dried under reduced pressure to produce 7-acetyl-6,14-endoetheno tetrahydrothebaine in a yield of 92%. The 7-acetyl-6,14-endoetheno tetrahydrothebaine is then dissolved in ethanol and hydrogenated with 5% palladium on charcoal catalyst for 30 hours at room temperature and a pressure of 60 psig. After removal of the catalyst, 7-acetyl-6,14-endoethano tetrahydrothebaine is obtained at only 80% yield by recrystallization of formed product from ethanol. The product 7-acetyl-6,14-endoethano tetrahydrothebaine is then converted to buprenorphine using a series of additional reaction steps.
As illustrated by the process detailed in the '915 patent, the amount of time required to conduct the Diels-Alder reaction and the hydrogenation reaction according to prior processes is undesirably high. In addition, the requirement in the prior processes for removal of excess methyl vinyl ketone has the potentially detrimental consequences of increasing the chance of exposing workers to methyl vinyl ketone, which is a hazardous substance. Also, a relatively complex series of steps is required to recrystallize 7-acetyl-6,14-endoethano tetrahydrothebaine from the hydrogenation reaction mixture and to remove the relatively large amount of epimeric impurity formed in the process. Also, the yield of 80% in the hydrogenation step is too low.